Nitric Oxide / Routine Split

[Viral]

Hey YJ,

I'm curious to get ur opinion along with any knowledge you may have about NO products in general, and any preferred ones if any underneath that. I see tons and tons, bottles on top of bottles, creatines + Nitris Oxides, just thousands of products that deal with NO. What do u know about NO and how beneficial can a product be? In that, which one would u suggest.

Besides that, when ur working out, how do u split up ur on/off days. Ive always gone 5 on 2 off in the past. But the past month or so ive been doing 3 on 1 off, they both worked well but I like the 3 on 1 off better.

--Thnx!

[YellowJacket]

This research (Thanks sphlonged) showed me enough to prove my speculations correct on all NO products:

You're better off with regular creatine, here's why:


The effectiveness of A-AKG in increasing NO
I did some research on this as well. AKG is metabolized into glutamate, which is then metabolized into L-glutamine (2). But this does not mean that it is nothing more than L-glutamine, remember that glutamate is the intermediary step.

Coincidentally... while researching fibromyaglia, I found that many cases of FM can be cured by eliminating MSG from the diet. MSG metabolizes to glutamate, which is an "excitotoxin," meaning it activates the NMDA receptors to the point of neural damage. And guess what... that leads to excessive nitric oxide levels (1). In other words, AKG does not work synergistically with arginine per se. It operates via a seperate mechanism to increase NO levels, and a potentially dangerous one. Ornithine-AKG has the same effect (2). I couldn't find any human studies regarding the safety of AKG, but I did find in many places (none of them "legitimate" though) that no such studies exist.

In light of this, I have developed a theory. The theory is that in NO2 and related products, the AKG is the important part and the arginine is just there for show (as opposed to what many people who criticize the products think, which is that the AKG is the useless part). I have been trying to find evidence to support this by finding references that say dietary arginine does not raise NO levels. What I've found so far:

-Every time NO levels go up, there is an increase in arginine disposal, which would imply that the body only uses what it needs based on other controlling mechanisms (such as the NMDA part of the brain) (3).
-Two analogues of arginine, ADMA and L-NMMA, are formed when there are excess amounts of arginine in cells. Both of these analogues inhibit the synthesis of more nitric oxide. In other words, whenever the body has enough arginine, it sends a message to slow production of nitric oxide.
-The only studies I found showing that administration of arginine increased NO levels was in cases of deficiency.

If anybody has more references on this, please let me know.

David

1. Smith J. D., Terpening C. M., Schmidt S. O. F., Gums J. G. Relief of fibromyalgia symptoms following discontinuation of dietary excitotoxins. Ann Pharmacotherapy 2001;35:702-706.
2. Le Boucher J et al., Enteral administration of ornithine alpha-ketoglutarate or arginine alpha-ketoglutarate: a comparative study of their effects on glutamine pools in burn-injured rats, Crit Care Med 1997 Feb;25(2):293-8
3. Bruins MJ, Lamers WH, Meijer AJ, Soeters PB, Deutz NE. In vivo measurement of nitric oxide production in porcine gut, liver and muscle during hyperdynamic endotoxaemia. Br J Pharmacol 2002 Dec;137(8):1225-36


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NO2 Exposed - Part 2


There are now quite a few supplements out there that claim to increase nitric oxide levels in the body. Examples include NO2, Nitro AKG, and NOX2. For the moment, I'm going to assume that these substances increase nitric oxide levels above the normal levels found in an otherwise healthy individual. What would this do?

The main functions of NO in various systems are listed here:

Immune system: Macrophages produce NO to kill target cells because it is cytotoxic. It disrupts the Kreb's cycle, DNA synthesis, and mitochondrial function, making it a very effective cell killer.

Nervous system: Acts as a neurotransmitter and regulates apoptosis (cell death) in neurons. NO is also correlated with the excitation of NMDA receptors.

Circulatory system: NO stimulates the production of pro-inflammatory compounds (specifically, eiconosoids), and other pro-inflammatory compounds are known to stimulate the production of NO. NO is also a vasiodilator.

I could find no evidence or reasons to believe than NO will cause gains in strength. If anybody has any, please let me know. The "pump" effect that many report could be due to vasiodilation (assuming the supplement increases NO levels).

Of prime importance here is the function of NO in the immune and nervous systems. I'll try to dumb this down as much as I can. O2-, or super-oxide, is the most prevalent oxidant in the body. That means: it's bad for you. Luckily, it is not very stable. ONOO- (peroxynitrite) is another oxidant, but is much more stable. So while super-oxide can do damage, peroxynitrite can do much more. On top of that, it can pass freely through cell membranes. When super-oxide reacts with NO, it forms peroxynitrate.

In the immune system, macrophages kill target bacteria and tumor cells through a targetted release of NO, which reacts with super-oxide to form peroxynitrite. This peroxynitrite then kills the targetted bacterium or cancer cell. So basically your immune system's defense is: poison the target cell.

This point should not be taken lightly. The more NO there is in your bloodstream, the more NO reacts with super-oxide to form peroxynitrite. But in this case, it's not a controlled response like immune response or apoptosis in neurons.

Now here's what makes the situation even worse. Under normal circumstances, the amount of NO in your system is closely mediated. There are three types of NOS (nitric oxide synthase, which produces NO in the body), and each responds to different things (such as the amount of calcium in cells). But like I said, let's assume that you can increase NO levels above normal. As described above, this causes peroxynitrite levels to go up. But peroxynitrate acts through six mechanisms to increase the levels of nitric oxide and super-oxide even more - which in turn produces more peroxynitrite. This is why peroxynitrate is such a potent cell killer; it reproduces itself. Once peroxynitrite levels hit a certain point, they will be self-sustaining (1).

To summarize: when NO levels hit a certain point, there can be a permanent increase in peroxynitrite levels. This, in turn, increases your chances of a variety of ailments. Some are described below.

Fibromyalgia (FM): Causes pain in all the fibrous tissues in the body, including muscles, ligaments, and tendons. The pain can be incapacitating. It is also associated with oxidative damage. Studies show excessive levels of nitric oxide and peroxynitrite as well as excessive activity in the NMDA system (in the brain) in FM patients. Nitric oxide stimulates nociceptors, neurons that cause the sensation of pain, and peroxynitrite does as well, which could quite possibly be the primary mechanism of action in this illness (2).

Chronic Fatigue Syndrome (CFS):Incapacitating fatigue, joint pain (similar to FM pain), inability to concentrate, and flu-like symptoms. Like FM, this is associated with elevated levels of nitric oxide.

Multiple Chemical Sensitivity (MCS): A controversial condition where people have negative responses to sub-toxic levels of various chemicals. Also associated with high nitric oxide levels.

All three of these conditions are chronic, and all three of them are related. They can all develop over a long period of time. What's even more surprising is all three of them are treated with vitamin B12 injections. Coincidentally, B12 is a potent nitric oxide scavenger (3).

I know that in my case, at least, I am no longer going to search for ways of artifically increasing nitric oxide levels. There's no evidence that it increases muscle strength, and there's no evidence that the "pump" is due to anything other than vasiodilation. What's more, there's plenty of evidence that messing with your body's normal balance of NO will do more harm than good.

David

1. Pall ML. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Medical Hypotheses 2000;54:115-125.
2. Pall M. L. Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite. Med Hypoth 2001;57:139-145.
3. Pall M. L. Cobalamin used in chronic fatigue syndrome therapy is a nitric oxide scavenger. J Chronic Fatigue Syndr 2001:8(2);39-44.

From shpongled

L-Arginine's function is a precursor to NO. It is not selectively used by iNOS, eNOS, or nNOS, to my knowledge. Since it enters the bloodstream during digestion, perhaps it is primarily utilized by eNOS. Either way, we can be sure that arginine does not increase NOS, just makes more of the NO precursor available to it.

My purpose in this post is to explore ways in which alpha-ketoglutarate (AKG) might increase NO production.

The first step is figuring out as much as I can - or what's relevant at least - about where AKG comes from and it's action on the body. To avoid confusing people too much, O-AKG and OKG are both names for ornithine alpha-ketoglutarate, and A-AKG is arginine alpha-ketoglutarate. To the best of my knowledge arginine and orginine are "carriers" and the body breaks them down separately into the amino acid and AKG. If anyone knows more about this, please let us know.

AKG is, in fact, naturally found in the body as an intermediate in the Kreb's cycle. But like nitric oxide, that does not mean an artifically large amount is a good thing. The body makes AKG when it needs it, where it needs it by itself. In some cases there is deficiency, but rarely in the general population.

AKG is the carbon skeleton of the amino acid glutamate. The rate at which AKG metabolizes into glutamate is relatively slow, so AKG could have an effect on the body independent of glutamate. A new study I found shows that AKG has a unique effect on the body. Some quotes from the study:

"OKG is usually recognized as generating glutamine, arginine and polyamines.... Inhibition of glutamine synthetase showed that glutamine production was not involved in the action of OKG. The use of S-methylthiourea and difluoromethylornithine demonstrated that OKG modulated the respiratory burst via nitric oxide (NO*) and polyamine generation. Moreover, OKG stimulated PMN migration via NO*, but arginine administration failed to reproduce this effect. These data suggest that OKG (or its metabolites) and arginine are channelled differently in PMNs. This hypothesis deserves further study."

As you can see, the effects of dietary AKG, the compound in all these NO products, is barely understood. Only a few things about it are known. It could have a variety of positive and negative benefits in different doses. So, since we know AKG breaks down into glutamate for sure, there are two possible compounds that exhibit toxic effects:

-AKG
-Glutamate

We know that excess amounts of glutamate can do quite a bit of damage to begin with. So we'll take a look at that first.

Glutamate, at first glance, seems like it couldn't be toxic at all. It's the most common excitatory neurotransmittor, and essential for brain function. Another name for glutamate is glutamic acid - a nonessential amino acid. They are essentially the same, although glutamate technically is an anion of glutamic acid. Whey protein is about 10% L-glutamic acid. Since L-glutamic acid is nonessential, it is very likely that additional supplementation can do more harm than good. A VERY interesting read on glutamine, glutamate etc. is here:

http://www.dietsexercise.com/glutamine-text4.htm
From this text:

quote:
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Glutamate is our chief excitatory neurotransmitter. It is essential for learning and both short-term and long-term memory. Problems arise only if the normal process of glutamate removal and conversion to glutamine malfunctions and an excess of this excitatory neurotransmitter builds up in the synaptic junctions. Excess glutamate causes excessive influx of calcium ions into the neurons causing excitotoxicity and ultimately even death of the neurons. It also destroys glutathione - a crucial brain-protective antioxidant. Low levels of brain glutathione are associated with neurodegenerative disorders. Glutathione depletion further leads to neuronal death.
Under what conditions do we see excess levels of glutamate at the synapses? Not surprisingly, we see evidence of damage associated with excess glutamate in Alzheimer's, AIDS patients, and cancer patients. The AIDS virus inhibits glutamate uptake by the glia. According to one hypothesis, cancer starts with brain dysfunction and in those who have suffered a severe brain injury. Very high fever or artificially induced hyperthermia can also result in excess glutamate release, leading to seizures.
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Over-stimulation of glutamate receptors is ALSO associated with Lou Gehrig's Disease and epilepsy. This is quite a list of conditions so far.

Confused at first (because it seems dietary glutamate doesn't have much of an effect on brain levels), I remembered that the glutamate from MSG was specifically implicated in CFS/FM etc. I stumbled upon this (warning: politically motivated?) website: http://www.truthinlabeling.org/msgfacts.html. A quote: "MSG-sensitivity is a sensitivity to free glutamic acid that occurs in food as a consequence of manufacture. All protein contains glutamic acid bound in it, but only when glutamic acid has been freed from protein before it is eaten do people have MSG-sensitivity reactions, provided that they ingest amounts that exceed their individual tolerance levels. Some unadulterated protein may have minute amounts of free glutamic acid associated with it, but MSG-sensitive people do not generally report adverse reactions following ingestion of unadulterated protein."

Another: "The names of most other MSG-containing ingredients won't give consumers even a clue to the fact that the ingredients contain MSG. "Monosodium glutamate," "monopotassium glutamate," "autolyzed yeast," "hydrolyzed soy protein," and "sodium caseinate," are examples of ingredients that always contain MSG." It seems hydrolyzed protein sources are especially implicated, which makes sense because they contain aminos in their free form.

What I think, at this point, is that glutamic acid in a protein source is harmless. However, free form glutamic acid can somehow disrupt the levels of glutamate in the brain, causing over-excitation of neurotransmittors. This might be a good reason why hydrolyzed protein sources might not be so great after all. So basically I've come full circle: back to AKG. If it's arginine-AKG or ornithine-AKG, I would logically think it wouldn't qualify as "free form." So, back to looking at how these substances metabolize.

Remember that above I stated that OKG metabolizes into glutamate, but doesn't seem to effect L-glutamine levels. This is where the pieces start to fit together. Another quote from the L-glutamine article (2):

quote:
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However, the use of glutamine as a free amino acid has never been associated with any form of brain damage. Glutamine is in fact abundantly produced in the brain as a vital defense against ammonia and also against excess glutamate. The main defense against glutamate excitotoxicity is the synthesis of glutamine by cells called the glia, or more specifically, astroglia or astrocytes. They are most abundant type of cell in the central nervous system exhibiting high amounts of glutamine synthase. The healthy brain is very well equipped to deal with glutamate. But, when the brain is damaged due to stroke or injury or the accumulation of various neurotoxins including certain drugs, the stage is set for glial dysfunction and hence for glutamate excitotoxicity.
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So... here's where the unique effects of AKG come into play. Normally, excess glutamate is readily metabolized into glutamine, which protects against the neurotoxicity. But somehow, O-AKG (and A-AKG as well I'm assuming) increase glutamate levels without the corresponding increase in glutamine. Through some mechanism, they bypass the body's primary defense against excess glutamate.

This is how glutamate levels are increased in the brain. This is universally accepted as a bad thing. This is how AKG can excite the NMDA receptors, leading to excess levels of nitric oxide. In a future post, I'll look at that more closely. I think it's safe to say, at this point, that this can be taken as a given:

-Arginine AKG and Ornithine AKG increase levels of glutamate above normal. Consumption of glutamic acid in protein or L-glutamine will not do this. Consumption of free-form glutamic acid *may* do this, but that issue is no longer relevant.
-The above-normal levels of glutamate would explain the excess amount of nitric oxide when these supplements are taken.

That's all for now. Sorry if this is disjointed, I typed as I researched and then went back and did a small amount of editing.

David

1. Moinard C et al., Effects of ornithine 2-oxoglutarate* on neutrophils in stressed rats: evidence for the involvement of nitric oxide and polyamines. Clin Sci (Lond) Mar 2002; 102(3):287-95 (*2-oxoglutarate = OKG)
2. http://www.dietsexercise.com/glutamine-text4.htm

[YellowJacket]

I, like you, prefer the 3 on 1 off method. If my schedule is getting hectic, Ill work in another muscle group and take 3 days off in the week. On weeks there's no way I can get 4 days in of lifting (which is happening a lot lately), Ill lift 3 days, and work in compound, multi-joint lifts and make sure my time in the gym is spent training and not concentrating on auxillary lifts.